Optically active amines are useful in asymmetric synthesis of organic compounds. For example, optically active bases such as (+)- and (-)-ephedrine, (-)-2-amino-1-butanol, (+)- and (-)-.alpha.-methylbenzylamine, (+)-amphetamine or (+)-deoxyephedrine are used extensively as resolving agents (Jacques, J., Collet, A. and Wilen, S. H. 1981. Enantiomers, Racemates, and Resolutions, 253-255. New York: John Wiley & Sons). In addition, chiral amines are useful in the preparation of asymmetric catalysts (Asymmetric Synthesis, 27-29. Ed. Morrison, J. D. Orlando, Fla.: Academic Press, Inc.).
Optically active amines are also of use as intermediates in the preparation of pharmaceutical agents and are of values as therapeutic agents themselves. For example, many biogenic amines and the various synthetic analogs thereof are .beta.-arylethylamines, e.g., dopamine when aryl is 3,4-dihydroxyphenyl. Substitution at the .alpha.- or .beta.-carbon of the ethylamine parent structure creats an asymmetric center and it is usual for one of the two stereoisomers to possess the greater activity.
Dopamine, a catecholamine with both adrenergic and dopaminergic receptor activity, is an important central neutrotransmitter. In addition, exogenous dopamine has found use clinically in the treatment of shock and chronic refractory heart failure (Goldberg, L. I., 1974, N. Engl. J. Med., 291, 707). Dopamine acts at .beta..sub.1 -receptors in the heart to exert cardiostimulatory effects and at .alpha..sub.1 -receptors in the vasculature to exert vasoconstriction. Dopamine also acts both centrally and peripherally at discrete dopaminergic receptors. Current dogma delineates dopaminergic receptors into two subclassifications, i.e., DA.sub.1 and DA.sub.2 receptor subtypes. Peripherally, DA.sub.1 receptors mediate vasodilitation of vascular smooth muscle and DA.sub.2 receptors mediate inhibition of norepinephrine release from postganglionic sympathetic nerves (Goldberg, L. I. and Kohli, J. D., 1983, Tends Pharmacol. Sci. 4, 64).
The .beta.-phenylethylamine parent structure of the sympathomimetic amines permits substitutions at the aromatic ring, the .alpha.- and .beta.-carbon atoms, and the terminal amino group. Such substitutions may affect activity or receptor selectivity. For example, hydroxy substitution of the .beta.-carbon can significantly enhance both .alpha.- and .beta.-adrenergic receptor activity, N-substituted amines may exhibit greater .beta.-adrenergic receptor activity, and substitutions on the .alpha.-carbon may block oxidation by monoamine oxidase thus enhancing the duration of action and oral activity (Gilman, A. G., Goodman, L. S., Rall, T. W. and Murad, F. 1985. The Pharmacological Basis of Therapeutics, 148-150. 7th ed. New York: Macmillan Publishing Company).
Several dopaminergic agonists have been described which act at DA.sub.1 and DA.sub.2 receptors but possess little or no adrenergic receptor activity. In that such compounds exhibit low activity at .alpha.- and .beta.-adrenergic receptors but retain activity at dopaminergic receptors, they have potential for use as anti-hypertensives or as afterload reducing agents in the treatment of congestive heart failure.
In addition to those optically active amines which are themselves useful as therapeutic agents, certain amines are useful as intermediates in the synthesis of pharmaceutically useful compounds. For example, (R)-2-(3,4-dimethoxybenzyl)pyrrolidine, disclosed in U.S. Pat. No. 4,279,918, is a key intermediate in the synthesis of certain orally active benzylpyrrolidene DA.sub.1 /DA.sub.2 receptor agonists, described in U.S. patent applications Ser. Nos. 07/369,366, titled "Bis(benzylpyrrolidine) Derivatives as Dopamine Agonists", filed Jun. 21, 1989, and 07/428,577, titled "Benzylpyrrolidine Derivatives as Dopamine Agonists", filed Oct. 30, 1989. Of the compounds described therein, (R)-2-(3,4-dihydroxybenzyl)-1-[6-(N-(3,4-dihydroxyphenethyl)-N-propylamino )hexyl]pyrrolidine and (R,R)-1,6-bis[2-(3,4-dihydroxbenzyl)pyrrolidin-1-yl]hexane are of particular interest.
Traditionally the preparation of optically active amines has been difficult and the process usually involves displacement of an activated optically active hydroxy group. Naturally, amino acids are a good source for optically active amines as starting materials. The amino acid may be reduced to form an aminoalcohol or larger molecules may be constructed with the use of various Grignard reagents, a step that necessitates the protection of the amine function of the amino acid (see processes described in U.S. patent applications Ser. Nos. 07/369,366 and 07/428,577).
The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.